Improving the Recovery and Outcome Every Day After the ICU

Primary Specific Aim: Determine the effect of the combined physical exercise and cognitive training on the cognitive function of ICU survivors aged 50 and older. Hypothesis: In comparison to older ICU survivors randomized to attention control or either intervention alone, those randomized to 12 weeks of combined physical exercise and cognitive training will have higher total index cognitive scores as assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) at 3 and 6 months post randomization. Secondary Specific Aim 1: Determine the effect of the combined physical exercise and cognitive training on physical performance, anxiety and depressive symptoms, and quality of life of ICU survivors aged 50 and older. Hypotheses: In comparison to older ICU survivors randomized to attention control or either intervention alone, those randomized to 12 weeks of combined physical exercise and cognitive training will have higher physical performance as measured by short physical performance battery (SPPB) and two-minute step test, lower mood and anxiety symptoms as measured by Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder (GAD-7) scale, and higher quality of life as measured by the Medical Outcomes Study 36-item short form (SF-36) at 3 and 6-months post randomization. Exploratory Aim 2: To examine the mechanisms of action of combined training. Hypothesis: At the completion of treatment, the combined intervention group will show reduced serum levels of CRP, IL-1, IL-6, IL-8, TNF-α, S-100β, and GFAP and increased levels of BDNF, VEGF, and IGF-1 compared to the attention control, or either intervention alone groups.

Critical illness has deleterious consequences on both acute and chronic cognitive functions. Acute cognitive dysfunction manifests itself as delirium in the critically ill especially the elderly. Delirium is a complex neuropsychiatric syndrome characterized by acute and fluctuating changes in cognition and consciousness. 60% to 80% of critically ill ventilated older patients and 30% to 50% of those with less illness severity have delirium for at least one day of their ICU or hospital stay. Chronic cognitive dysfunction manifests as ICU acquired cognitive impairment and dementia after critical illness, affects multiple cognitive domains and persists years after hospital discharge. Up to 71% of critical illness survivors have cognitive impairment at one year after hospital discharge and close to 18% are diagnosed with new dementia including Alzheimer's disease within three years post ICU hospitalization. Two million older Americans suffer from an episode of delirium during their intensive care unit (ICU) stay. Presence of delirium predisposes the elderly to immediate in-hospital complications including a longer length of ICU and hospital stay, increased risk of in-patient mortality and elevated costs of care. In addition, ICU delirium is associated with long-term post-discharge complications such as development of cognitive impairment and dementia. Current advances in the management of critical illness have notably improved the survival rates among this vulnerable segment of older adults. However, increased survival comes at a cost with as many as 70% of older ICU survivors who had an episode of delirium suffering from subsequent cognitive impairment and dementia. At present, there are no effective and scalable recovery models to remediate ICU acquired cognitive impairment and its attendant elevated dementia or Alzheimer's disease risk. The inability to develop efficacious interventions to reduce ICU acquired cognitive impairment may stem from a limited understanding of the link between acute brain dysfunction (delirium) and chronic brain dysfunction (ICU acquired cognitive impairment, dementia or Alzheimer's disease). The investigators propose a recovery intervention guided by the pathophysiologic mechanisms implicated in producing critical illness delirium and elevated risk of cognitive impairment. The intervention targets inflammation, glial dysfunction and astrocyte activation along with restoration of neurotrophic factors while training function directly across multiple cognitive domains to reduce the burden of cognitive impairment among ICU survivors of delirium. Over the past five years, Indiana University Center for Aging Research has developed a research infrastructure focused on delirium and delirium associated cognitive impairment, encompassing the ICU and post-ICU periods. This includes developing a bio-repository of serum delirium biomarkers, ICU based delirium trials, and post-ICU exercise and cognitive therapy recovery models. Building upon prior work and based on the pathophysiologic mechanisms mentioned above, the investigators now propose a novel home-based combined physical exercise and cognitive training program for older ICU survivors to improve cognitive impairment. The study team is proposing a 2x2 factorial design randomized controlled trial (RCT) called "Decreasing Alzheimer's Disease and Related Dementias after Delirium-Exercise and Cognitive Training (DDD-ECT)" to evaluate the efficacy of 12 weeks of combined physical exercise and cognitive training on the primary outcome of cognitive function among older ICU survivors who experienced delirium or subsyndromal delirium during their ICU stay. The investigators propose to deliver these interventions via a facilitator-led, small group format using internet-enabled, multiparty-videoconference delivered directly into the participants' homes to achieve the study aims listed in the summary.